Nck1 deficiency improves pancreatic β cell survival to diabetes-relevant stresses by modulating PERK activation and signaling

Yamani, Lama; Li, Bing; Larose, Louise

doi:10.1016/j.cellsig.2015.09.016

Cited by 21 publications

(26 citation statements)

References 69 publications

(111 reference statements)

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“…We demonstrated that Nck1 is essential for sustained hepatic activation of the IRE1a-JNK pathway associated with impaired glucose homeostasis secondary to obesity in mice (15). We also have showed that Nck1 modulates PERK-dependent regulation of insulin biosynthesis and survival in pancreatic b-cells (13,14). In the current study, we report that Nck2 is required to regulate PERK activity and signaling during adipogenesis and in mature adipocytes to prevent abnormal WAT expansion and dysfunction associated with metabolic disorders.…”

mentioning

confidence: 67%

“…MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] activity was assessed to determine cell number on days 1-4 after plating as previously described (14). Freshly isolated WAT SVF from both mouse genotypes were washed twice and incubated for 30 min at 4°C with the following antibodies: PE/Cy7 CD29 (clone HMb1-1; BioLegend 102221), allophycocyanin CD34 (clone HM34; BioLegend 128611), and Pacific Blue Sca-1 (clone D7; BioLegend 108119).…”

Section: Cell Proliferation and Flow Cytometry Analysismentioning

confidence: 99%

“…The UPR is initiated at the level of the endoplasmic reticulum (ER) by three ER transmembrane sensors: the doublestranded RNA-like ER kinase (PERK), Ser/Thr kinase/ endoribonuclease inositol-requiring enzyme-1a (IRE1a), and activating transcription factor 6 (ATF6) (9). We and others implicated Nck in regulating the UPR through its interaction with the b-subunit of the eukaryotic initiation factor 2 (eIF2b) (8,10,11), Ser/Thr phosphatase PP1 (8,12), PERK (13,14), and IRE1a (7). We demonstrated that Nck1 is essential for sustained hepatic activation of the IRE1a-JNK pathway associated with impaired glucose homeostasis secondary to obesity in mice (15).…”

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confidence: 99%

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Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis

Dusseault

Haider

et al. 2016

Diabetes

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Obesity results from an excessive expansion of white adipose tissue (WAT) from hypertrophy of preexisting adipocytes and enhancement of precursor differentiation into mature adipocytes. We report that Nck2-deficient mice display progressive increased adiposity associated with adipocyte hypertrophy. A negative relationship between the expression of Nck2 and WAT expansion was recapitulated in humans such that reduced Nck2 protein and mRNA levels in human visceral WAT significantly correlate with the degree of obesity. Accordingly, Nck2 deficiency promotes an adipogenic program that not only enhances adipocyte differentiation and lipid droplet formation but also results in dysfunctional elevated lipogenesis and lipolysis activities in mouse WAT as well as in stromal vascular fraction and 3T3-L1 preadipocytes. We provide strong evidence to support that through a mechanism involving primed PERK activation and signaling, Nck2 deficiency in adipocyte precursors is associated with enhanced adipogenesis in vitro and adiposity in vivo. Finally, in agreement with elevated circulating lipids, Nck2-deficient mice develop glucose intolerance, insulin resistance, and hepatic steatosis. Taken together, these findings reveal that Nck2 is a novel regulator of adiposity and suggest that Nck2 is important in limiting WAT expansion and dysfunction in mice and humans.

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confidence: 67%

Section: Cell Proliferation and Flow Cytometry Analysismentioning

confidence: 99%

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confidence: 99%

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Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis

Dusseault

Haider

et al. 2016

Diabetes

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“…Nonetheless, study found that the expression of autophagy signature proteins, LC3/Atg8 and Atg7, was decreased in aging islet cells. Similarly, the autophagy function of islets in aged rats was found to decrease [154]. Upregulation of P16ink4a/p19ARF expression, decrease in bmi-1 and EZH2 levels, and abnormal regulation of platelet-derived growth factor signals are important factors leading to a decline in the proliferation and insulin secretion of age-related β cells [155,156].…”

Section: Diabetes Mellitusmentioning

confidence: 92%

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

Liu

Wei-liang

Gao

et al. 2019

Oxidative Medicine and Cellular Longevity

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Aging is a progressive disease affecting around 900 million people worldwide, and in recent years, the mechanism of aging and aging-related diseases has been well studied. Treatments for aging-related diseases have also made progress. For the long-term treatment of aging-related diseases, herbal medicine is particularly suitable for drug discovery. In this review, we discuss cellular and molecular mechanisms of aging and aging-related diseases, including oxidative stress, inflammatory response, autophagy and exosome interactions, mitochondrial injury, and telomerase damage, and summarize commonly used herbals and compounds concerned with the development of aging-related diseases, including Ginkgo biloba, ginseng, Panax notoginseng, Radix astragali, Lycium barbarum, Rhodiola rosea, Angelica sinensis, Ligusticum chuanxiong, resveratrol, curcumin, and flavonoids. We also summarize key randomized controlled trials of herbal medicine for aging-related diseases during the past ten years. Adverse reactions of herbs were also described. It is expected to provide new insights for slowing aging and treating aging-related diseases with herbal medicine.

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“…[26][27][28] Within this context, we identified a major role for Nck in regulating signaling from the ER through direct interaction with IRE1-a (Inositol-required enzyme 1-a) and PERK (double-stranded RNA-like ER kinase), [28][29][30][31][32] 2 fundamental components of the unfolded protein response (UPR), whose dysregulation has been implicated in the development of obesity. 33 It is noteworthy that obesity creates ER stress inducing sustained activation of the UPR in liver and adipose tissue, 34,35 potentially through increased production of reactive oxygen species 35 and impaired Ca 2C homeostasis.…”

Section: A Critical Role For Nck2 In Regulating Adipogenesismentioning

confidence: 99%

Nck2, an unexpected regulator of adipogenesis

et al. 2017

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The regulation of adipose tissue expansion by adipocyte hypertrophy and/or hyperplasia is the topic of extensive investigations given the potential differential contribution of the 2 processes to the development of numerous chronic diseases associated with obesity. We recently discovered that the loss-of-function of the Src homology domain-containing protein Nck2 in mice promotes adiposity accompanied with adipocyte hypertrophy and impaired function, and enhanced adipocyte differentiation in vitro. Moreover, in severely-obese human's adipose tissue, we found that Nck2 expression is markedly downregulated. In this commentary, our goal is to expand upon additional findings providing further evidence for a unique Nck2-dependent mechanism regulating adipogenesis. We propose that Nck2 should be further investigated as a regulator of the reliance of white adipose tissue on hyperplasia versus hypertrophy during adipose tissue expansion, and hence, as a potential novel molecular target in obesity.

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Nck1 deficiency improves pancreatic β cell survival to diabetes-relevant stresses by modulating PERK activation and signaling

Cited by 21 publications

References 69 publications

Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis

Nck2 Deficiency in Mice Results in Increased Adiposity Associated With Adipocyte Hypertrophy and Enhanced Adipogenesis

New Insights for Cellular and Molecular Mechanisms of Aging and Aging-Related Diseases: Herbal Medicine as Potential Therapeutic Approach

Nck2, an unexpected regulator of adipogenesis

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